O(^3P) +CO_2 Collisions at Hyperthermal Energies: Dynamics of Nonreactive Scattering, Oxygen Isotope Exchange, and Oxygen-Atom Abstraction

The dynamics of O(^3P) + CO_2 collisions at hyperthermal energies were investigated experimentally and theoretically. Crossed-molecular-beams experiments at Ecoll = 98.8 kcal mol^(–1) were performed with isotopically labeled ^(12)C^(18)O_2 to distinguish products of nonreactive scattering from those of reactive scattering. The following product channels were observed: elastic and inelastic scattering (^(16)O(^3P) + ^(12)C^(18)O^2), isotope exchange (^(18)O + ^(16)O^(12)C^(18)O), and oxygen-atom abstraction (^(18)O^(16)O + ^(12)C^(18)O). Stationary points on the two lowest triplet potential energy surfaces of the O(^3P) + CO_2 system were characterized at the CCSD(T)/aug-cc-pVTZ level of theory and by means of W4 theory, which represents an approximation to the relativistic basis set limit, full-configuration-interaction (FCI) energy. The calculations predict a planar CO_3(C_(2v),^3A″) intermediate that lies 16.3 kcal mol^(–1) (W4 FCI excluding zero point energy) above reactants and is approached by a C_(2v) transition state with energy 24.08 kcal mol^(–1). Quasi-classical trajectory (QCT) calculations with collision energies in the range 23–150 kcal mol^(–1) were performed at the B3LYP/6-311G(d) and BMK/6-311G(d) levels. Both reactive channels observed in the experiment were predicted by these calculations. In the isotope exchange reaction, the experimental center-of-mass (c.m.) angular distribution, T(θ_(c.m.)), of the ^(16)O^(12)C^(18)O products peaked along the initial CO_2 direction (backward relative to the direction of the reagent O atoms), with a smaller isotropic component. The product translational energy distribution, P(E_T), had a relatively low average of E_T = 35 kcal mol^(–1), indicating that the ^(16)O^(12)C^(18)O products were formed with substantial internal energy. The QCT calculations give c.m. P(E_T) and T(θ_(c.m.)) distributions and a relative product yield that agree qualitatively with the experimental results, and the trajectories indicate that exchange occurs through a short-lived CO_3^* intermediate. A low yield for the abstraction reaction was seen in both the experiment and the theory. Experimentally, a fast and weak ^(16)O^(18)O product signal from an abstraction reaction was observed, which could only be detected in the forward direction. A small number of QCT trajectories leading to abstraction were observed to occur primarily via a transient CO_3 intermediate, albeit only at high collision energies (149 kcal mol^(–1)). The oxygen isotope exchange mechanism for CO_2 in collisions with ground state O atoms is a newly discovered pathway through which oxygen isotopes may be cycled in the upper atmosphere, where O(^3P) atoms with hyperthermal translational energies can be generated by photodissociation of O_3 and O_2

Phase 1, first-in-human study of TYRP1-TCB (RO7293583), a novel TYRP1-targeting CD3 T-cell engager, in metastatic melanoma: active drug monitoring to assess the impact of immune response on drug exposure

Antibody; Immunogenicity; Metastatic melanomaAnticuerpos; Inmunogenicidad; Melanoma metastásicoAnticossos; Immunogenicitat; Melanoma metastàticIntroduction: Although checkpoint inhibitors (CPIs) have improved outcomes for patients with metastatic melanoma, those progressing on CPIs have limited therapeutic options. To address this unmet need and overcome CPI resistance mechanisms, novel immunotherapies, such as T-cell engaging agents, are being developed. The use of these agents has sometimes been limited by the immune response mounted against them in the form of anti-drug antibodies (ADAs), which is challenging to predict preclinically and can lead to neutralization of the drug and loss of efficacy. Methods: TYRP1-TCB (RO7293583; RG6232) is a T-cell engaging bispecific (TCB) antibody that targets tyrosinase-related protein 1 (TYRP1), which is expressed in many melanomas, thereby directing T cells to kill TYRP1-expressing tumor cells. Preclinical studies show TYRP1-TCB to have potent anti-tumor activity. This first-in-human (FIH) phase 1 dose-escalation study characterized the safety, tolerability, maximum tolerated dose/optimal biological dose, and pharmacokinetics (PK) of TYRP1-TCB in patients with metastatic melanoma (NCT04551352). Results: Twenty participants with cutaneous, uveal, or mucosal TYRP1-positive melanoma received TYRP1-TCB in escalating doses (0.045 to 0.4 mg). All participants experienced ≥1 treatment-related adverse event (TRAE); two participants experienced grade 3 TRAEs. The most common toxicities were grade 1–2 cytokine release syndrome (CRS) and rash. Fractionated dosing mitigated CRS and was associated with lower levels of interleukin-6 and tumor necrosis factor-alpha. Measurement of active drug (dual TYPR1- and CD3-binding) PK rapidly identified loss of active drug exposure in all participants treated with 0.4 mg in a flat dosing schedule for ≥3 cycles. Loss of exposure was associated with development of ADAs towards both the TYRP1 and CD3 domains. A total drug PK assay, measuring free and ADA-bound forms, demonstrated that TYRP1-TCB-ADA immune complexes were present in participant samples, but showed no drug activity in vitro. Discussion: This study provides important insights into how the use of active drug PK assays, coupled with mechanistic follow-up, can inform and enable ongoing benefit/risk assessment for individuals participating in FIH dose-escalation trials. Translational studies that lead to a better understanding of the underlying biology of cognate T- and B-cell interactions, ultimately resulting in ADA development to novel biotherapeutics, are needed.The author(s) declare financial support was received for the research, authorship, and/or publication of this article

Long-term clinical outcomes of repeat hysteroscopic endometrial ablation after failed hysteroscopic endometrial ablation

The study aims to describe patient characteristics, uterine cavity shape and histopathology, complications, and long-term clinical outcomes of women who failed hysteroscopic rollerball or loop endometrial ablation (HEA) and subsequently consented to repeat hysteroscopic endometrial ablation (RHEA), and is a retrospective cohort study (Canadian Task Force classification II-2). The study was conducted in the university-affiliated teaching hospital. Patients included women who failed primary hysteroscopic endometrial ablation (PHEA, n = 183) and subsequently underwent RHEA by the senior author (GAV) from 1993 through 2007 with a minimum follow-up of 5 years. RHEA was performed under general anesthesia using 26 F (~9 mm) resectoscope, monopolar loop electrode in 136 (74.3 %), 3–5 mm rollerball in 41 (22.4 %) or combination in 6 (3.3 %) women. Patient characteristics, uterine cavity, and clinical outcomes of women who failed PHEA and subsequently consented to RHEA were evaluated by retrospective chart review and patient follow-up including office visits and/or telephone interview. The corresponding median age (range) for PHEA and RHEA was 40 (26–70) and 43 (29–76) years. Indications for PHEA included abnormal uterine bleeding (AUB, 52.7 %), AUB and dysmenorrhea (25.8 %), dysmenorrhea (18.8 %), and others (2.7 %). Indications for RHEA included persistent AUB (53 %), AUB and uterine/pelvic pain (26.2 %), uterine/pelvic pain only (19.1 %), postmenopausal bleeding (1.1 %), and thickened endometrium (0.5 %). Complications of RHEA (n = 7, 3.8 %) included false passage (3), uterine perforation (2), and bleeding (2). One patient with excessive bleeding required immediate hysterectomy. At a median follow-up of 9 years (5–19), 69 % of women avoided hysterectomy. Repeat hysteroscopic endometrial ablation is a feasible, safe, and long-term effective alternative to hysterectomy for abnormal uterine bleeding from benign causes when performed by experienced surgeons

Still pictures, animations or interactivity – What is more effective for elearning?

Over recent years information and communications technology has increasingly been incorporated into teaching activities in higher education. As a consequence best practices for design of multimedia instructional materials and for establishing effective e-learning environments have been investigated. It has been shown that concurrent presentation of text with either animations or pictures can enhance learning (Mayer and Moreno, 1998) and that multimedia materials which include interactive elements may lead to enhanced student engagement (Craincross and Mannion 2001; Littlejohn, Suckling, Campbell and McNicol 2002). Higher quality learning occurs when students are actively and cognitively involved with the learning process, and engagement promotes such involvement (Scott 2001). Design must be based on the needs and interests of the user and the limitations and capabilities of multimedia need to be understood well, before the potential benefits can be realised (Craincross and Mannion 2001). What we believe, as academics, will assist students in their learning, may not necessarily do that. However, evidence addressing the effectiveness of different approaches for promoting engagement with multimedia technology remains limited. In this context we have started to develop online learning materials for use as pre-laboratory instruction or stand-alone learning modules for first year chemistry students. To inform development at an early stage a study was undertaken to investigate the most effective design of online chemistry modules for enhancing student learning and addressing misconceptions. Initially we have developed three different versions of an online chemistry module: • one that used still pictures and text only (Static version); • one that used animations/simulations and text (Animated version); and • one that used animations/simulations, text and interactivity (Interactive version). The outcomes of this study are of significant interest for this institution and beyond, since students often use online learning as a supplement to lectures. If one particular method of delivery is more effective than another, then such information is likely to have a significant impact on the design of online materials in the future. Not only can this information help enhance student performance, it can allow the process to be more efficient and cost effective. The results reported in the following draw on student surveys and participants’ assessment results

Testing the personalisation hypothesis in pre-laboratory e-learning environments

Computer-based multimedia learning environments have been expected to offer a powerful and effective means of improving student learning and understanding (Mayer and Moreno 2002). In recent times, there has been much research activity investigating best practices for design of multimedia instructional materials and for establishing effective e-learning environments. Several principles of design for fostering multimedia learning have been established and tested such as the multiple representation principle – it is better to present explanations as words and pictures rather than solely as words and coherence principle – people learn better when extraneous words, pictures and sounds are excluded rather than included (Harp and Mayer 1998; Mayer and Moreno 2002)

Increasing students’ interest and motivation through effective design of online learning environments

The literature on the use of information and communications technology over recent years has been concerned with best practices for the design of multimedia instructional materials. A range of tools and teaching materials are used to develop students’ understanding in different domains. However, evidence addressing the effectiveness of using multimedia, especially interactive elements, remains limited. The present study investigates how the graphics interface of an online environment can be used to effectively present first year chemistry material. In order to conduct this research we developed an online chemistry module with three different versions. Students’ performance associated with using these different versions was examined. The information gained from this study will help to improve the graphics interface of online learning environments and is likely to have a significant impact on improving student learning

The personalisation hypothesis in e-learning: Further developments

Student learning and understanding has the potential to improve with the use of computer-based multimedia environments. Such environments have been expected to offer a powerful effective means of delivering material and enhancing learning (Mayer and Moreno 2002). Presently, there is much research activity investigating best practices for the design of multimedia instructional materials for creating effective e-learning environments. Several principles have already been established and tested such as the multiple representation principle meaning that it is better to present explanations as words and pictures rather than solely words (Mayer and Moreno 2002)

Bis[(1S*,2S*)-trans-1,2-bis­(diphenyl­phosphin­oxy)cyclo­hexa­ne]chlorido­ruthenium(II) trifluoro­methane­sulfonate dichloro­methane disolvate

The crystal structure of a racemic mixture of the title ruthenium(II) complex, [RuCl(C30H30O2P2)2]CF3SO3·2CH2Cl2, reveals that the coordination geometry about the coordinatively unsaturated metal centre is approximately trigonal-pyramidal, with the chlorine atom occupying one of the equatorial positions. The axial Ru—P bonds are longer than the equatorial Ru—P bonds and there is an acute P—Ru—P angle

Nanostructured Bimetallic Block Copolymers as Precursors to Magnetic FePt Nanoparticles

Phase-separated block copolymers (BCPs) that function as precursors to arrays of FePt nanoparticles (NPs) are of potential interest for the creation of media for the next-generation high-density magnetic data storage devices. A series of bimetallic BCPs has been synthesized by incorporating a complex containing Fe and Pt centers into the coordinating block of four different poly­(styrene-<i>b</i>-4-vinylpyridine)­s (PS-<i>b</i>-P4VPs, <b>P1–P4</b>). To facilitate phase separation for the resulting metalated BCPs (<b>PM1–PM4</b>), a loading of the FePt-bimetallic complex corresponding to ca. 20% was used. The bulk and thin-film self-assembly of these BCPs was studied by transmission electron microscopy (TEM) and atomic force microscopy, respectively. The spherical and cylindrical morphologies observed for the metalated BCPs corresponded to those observed for the metal-free BCPs. The products from the pyrolysis of the BCPs in bulk were also characterized by TEM, powder X-ray diffraction, and energy-dispersive X-ray spectroscopy, which indicated that the FePt NPs formed exist in an fct phase with average particle sizes of ca. 4–8 nm within a carbonaceous matrix. A comparison of the pyrolysis behavior of the metalated BCP (<b>PM3</b>), the metalated <b>P4VP</b> homopolymer (<b>PM5</b>), and the molecular model organometallic complex revealed the importance of using a nanostructured BCP approach for the synthesis of ferromagnetic FePt NPs with a smaller average NP size and a close to 1:1 Fe/Pt stoichiometric ratio